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Neuroendocrine Cancer Syndromes – Early Signs of a Late Diagnosis

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Early signs of a late diagnosis

it’s not all about ‘Carcinoid’

One of the curious things about Neuroendocrine Cancer (NET Cancer) is that it can exhibit one or more vague symptoms collectively known as a ‘syndrome’.  Syndrome is an apt word to describe these complications as the most general meaning in medical terms is a group of symptoms that together are characteristic of a specific disorder or disease”

It’s not all about Carcinoid Syndrome!

Most people think of Carcinoid Syndrome when they discuss NET Cancer. Anyone suggesting that all NET patients get carcinoid syndrome or that all symptoms of NETs are caused by carcinoid syndrome, is off the mark. Firstly, not everyone will have a ‘syndrome’ in addition to their tumours. Secondly, there are in actual fact, several associated syndromes depending on the location and type of NET Cancer. As an example of one syndrome, statistics vary from source to source but it is estimated that around a 30-45% of all ‘midgut’ patients will present with metastatic disease and around a third of those (∼10-15% of all midgut) will exhibit Carcinoid Syndrome indicating their tumours are functional (secreting excess hormones, particularly serotonin).  It follows that Carcinoid Syndrome itself is not that common and it could be the same with other types of NET Cancer (even though it can appear more prevalent on forums).

Diagnostic Challenges in NET Cancer (this graphic only covers so-called Carcinoid Syndrome).  Inner segments are the key symptoms, outer segments are some of the potential misdiagnosis/delayed diagnosis. Graphic courtesy of Modlin IM, Kidd M, Latich I, et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005; 128: 1717-1751

Functional / Non-Functional

These tumours and associated syndromes are treatable for most but the difficult part can be arriving at a diagnosis. Moreover, without a syndrome, some of these tumours can be silently growing and as they grow slowly, the ‘silence’ can go on for some years. Even with a syndrome, the root cause can remain disguised as the symptoms are similar to many day-to-day illnesses, again the reason for the title of this blog. Curiously, the lack of a syndrome can sometimes lead to an even later presentation and the consequences that arise (i.e. no signs to aid a diagnosis). In fact a large proportion of Pancreatic NETs are non-functional at diagnosis. There can be the odd exception but in general terms, NETs are either functional (with a syndrome) or non-functional (no syndrome). It’s also possible that patients can move from one state to another.

Syndrome and Tumors – ‘Chicken or Egg’ ?

I’m always confused when someone says they have been diagnosed with a Syndrome rather than a NET cancer type.  You normally need a tumor to produce the symptoms of a syndrome.

The exception might be hereditary syndromes e.g. MEN.  MEN syndromes are genetic conditions. This means that the cancer risk and other features of MEN can be passed from generation to generation in a family. A mutation (alteration) in the various MEN genes gives a person an increased risk of developing endocrine/neuroendocrine tumors and other symptoms of MEN. It’s also possible that the tumors will be discovered first.  It’s complex!

Major NET Syndromes  

(information mainly taken from the ISI Book on NETs with a cross-reference from ENETS and UKINETS Guidelines)

The ISI Book on Neuroendocrine Tumors 2016 (Woltering et al) confirms there are a number of syndromes associated directly and indirectly with NET Cancer and are described as individual syndromes according to their secretory hormones and peptides. The referenced publication expands on this list to aid diagnoses by including common presentations, associated tumour types and locations and the offending secreting hormones. You can see why NET Cancer is a diagnostic challenge!

Carcinoid – a syndrome connected with conventional carcinoid locations (mainly small intestine, lung, stomach, appendix, rectum). The key symptoms include diarrhoea, flushing of the skin (particularly the face), stomach cramping, heart problems such as palpitations, and wheezing. The syndrome is caused by the release of a number of hormones, in particular Serotonin, Bradykinin, Tachykinin (Substance P), Histamine, and Prostaglandins.

(there’s also a very rare instance of pancreatic based tumours producing carcinoid syndrome effects – according to ENETs less than 1% of all (so-called) ‘carcinoid tumours’)

Insulinoma (Whipple’s Triad) – Whipple’s Triad is the classic description of insulinoma which includes symptoms of hypoglycemia with a low blood glucose concentration relieved by the ingestion of glucose. These tumours can be located anywhere within the pancreas in the cells that make insulin. Insulin is a hormone that controls the amount of  glucose (sugar) in the blood. It moves glucose into the cells, where it can be used by the body for energy. Insulinomas are usually slow-growing tumors that rarely spread. Some of these tumours will be associated with MEN1 syndrome.

Zollinger-Ellinson Syndrome.  A tumour that forms in cells that make gastrin and can be known as a Gastrinoma. Gastrin is a hormone that causes the stomach to release an acid that helps digest food. Both gastrin and stomach acid are increased by gastrinomas.  This is a condition in which one or more tumours form in the pancreas, the upper part of the duodenum or the stomach (these organs are very close and tightly packed together). These tumours secrete large amounts of the hormone gastrin, which causes your stomach to produce too much acid. The excess acid can lead to peptic ulcers, in addition to diarrhea and other symptoms.  Associated with Gastrinoma (pNET) and Gastric NETs.  Some of these tumours may be associated with MEN1 syndrome.

Werner-Morrison SyndromeVasoactive Intestinal Peptide (VIP) is secreted thus the pNET term – VIPoma –  Sometimes the syndrome is referred as WDHA – Watery Diarrhea, Hypokalemia (potassium deficiency), and Achlorhydria (absence of hydrochloric acid in gastric secretions).  Sometimes known as Pancreatic Cholera. Some of these tumours may be associated with MEN1 syndrome

Glucagonoma.  A tumour that forms in cells that make make glucagon. Glucagon is a hormone that increases the amount of glucose in the blood. It causes the liver to break down glycogen. Too much glucagon causes hyperglycemia (high blood sugar). A glucagonoma usually forms in the tail of the pancreas.  Some of these tumours may be associated with MEN1 syndrome.  See also Sweet’s Syndrome below.

Somatostatinoma is a very rare type of NET, with an incidence of one in 40 million persons. These tumours produce excess somatostatin arise from the delta cells in the pancreas, although these cells can also be present in duodenal/jejunum tissue where around 44% of these tumours occur. Somatostatin is a naturally occurring peptide that inhibits the function of almost all gut hormones (author’s note – this fact should give you an appreciation of how somatostatin analogues tackle associated syndromes whilst giving you certain side effects as a result!)

Pancreatic Polypeptide (PP)PPoma.  A complicated one and not too much information (even in the ISI book or ENETS Guidelines). However, it’s the third most common type of islet cell tumour (i.e. pNET).  The function of pancreatic polypeptide is not completely understood. Patients present with weight loss, jaundice, and abdominal pain. The diagnosis is confirmed by pancreatic polypeptide levels > 300 pg/ml. Some of these tumours may be associated with MEN1 syndrome.

Hedinger Syndrome – the technical term for Carcinoid Heart Disease.

Cushing’s – also known as hypercortisolism.  A collection of symptoms caused by very high levels of a hormone called cortisol in the body.   In Cushing’s disease, oversecretion of pituitary ACTH induces bilateral adrenal hyperplasia. This results in excess production of cortisol, adrenal androgens, and 11-deoxycorticosterone. Cushing’s disease, a subset of Cushing’s syndrome, is due to a pituitary corticotroph adenoma and results in a partial resistance to the suppression of ACTH by cortisol so that secretion is unrestrained. In contrast, causes of Cushing’s syndrome may include the following:

•   Adrenal adenoma or carcinoma arise spontaneously. ACTH levels are undetectable.

•   Non-pituitary (ectopic) tumours produce ACTH. They most frequently originate in the thorax and are highly aggressive small cell carcinomas of the lung or slow- growing bronchial or thymic carcinoid tumours. Some produce corticotropin- releasing hormone (CRH) instead, which stimulates pituitary ACTH secretion and can therefore mimic a pituitary tumour.

•   Other causes include NETs of the gastric, pancreatic, and intestinal organs; Pheochromocytomas, and MCT.

The hallmark of Cushing’s syndrome is that ACTH levels are partially resistant to suppression with dexamethasone, even at very high doses. Some MEN patients with pituitary tumours may have Cushing’s Syndrome. AdrenoCorticoTropic Hormone (ACTH) releasing tumours are somerimes known as ACTHoma.

Sweet’s – Dermatitis/rash associated with Glucagonomas.  Not to be confused with Pellagra.

Neuroendocrine / Endocrine tumors can be seen in several inherited familial syndromes, including:

  • Multiple Endocrine Neoplasia type 1 (MEN1)
  • Multiple Endocrine Neoplasia type 2 (MEN2)
  • SDHx mutations/Hereditary Pheochromocytoma/Paraganglioma Syndromes
  • Von Hippel-Lindau (VHL) Disease
  • Neurofibromatosis Type 1 (also known as Recklinghausen’s Disease). Not covered further.
  • Tuberous Sclerosis (not covered further)
  • Carney Complex (see Genetics and Neuroendocrine Tumors)


MEN1 – Mainly involved the 3 Ps, Pituitary, Pancreas and Parathyroid.  The pituitary tumours are primarily Prolactinomas, the pancreatic tumours are mainly PPomas, Gastrinomas and Insulinoma.  Many also have association with Zollinger-Ellinson  syndrome (ZES). Read more here.  Sometimes known as Wermer Syndrome.

MEN2 (A & B) – including association with Medullary Thyroid Cancer (MTC) (including the familial type FMTC) and Pheochromocytoma/Paraganglioma and  Parathyroid hyperplasia.  Read more here.

SDHx mutations/Hereditary pheochromocytoma/paraganglioma syndromes

  • Succinate dehydrogenase (SDH) is an enzyme which is important for the metabolic function of mitochondria. Patients with mutations of these genes have increased risk of pheochromocytomas, paragangliomas, stomach tumors and kidney tumors.
  • SDHx mutations (SDHA, SDHB, SDHC, and SDHD) can present as Pheochromocytomas/Paragangliomas and other non-NET conditions.  If this interests you see site http://www.SDHcancer.org

Von Hippel-Lindau (VHL) – not an exclusively NET syndrome. VHL is a rare disorder caused by a faulty gene. It is named after the two doctors who first described the disease, and affects about one in 35,000 people. Tumours develop in one or more parts of the body. Many of these tumours involve the abnormal growth of blood vessels in parts of the body which are particularly rich in blood vessels. Areas most frequently affected are the eyes, the back of the brain (cerebellum), the spinal cord, the kidneys, the adrenal glands and the pancreas. People are affected differently, even within the same family. The only VHL tumour which tends to run in families affects the adrenal glands (Pheochromocytoma). Different VHL features tend to develop at different ages. The eye angiomas often develop in childhood. Others, including tumours found in the cerebellum, spinal cord or adrenal glands (Haemangioblastomas and Pheochromocytomas) can develop from late childhood onwards. The kidney tumours are usually the last things that develop, from the mid-twenties onwards.  Most VHL related tumours are benign.


As for my own experience of syndromes, I did once show symptoms of the most common NET syndrome (currently known as Carcinoid syndrome) where the key symptoms include diarrhoea, flushing of the skin (particularly the face), stomach cramping, heart problems such as palpitations, and wheezing.  You can see why those symptoms are frequently and easily confused with other conditions. If you have a similar diagnosis, you may benefit from looking at something known as The 5 E’s which is a useful list of things to be wary of.

I did have issues for a year or two in 2010 leading up to diagnosis and until my treatment was underway.  I was experiencing flushing and infrequent bouts of diarrhea but I totally ignored it (hear me talk about this). However, it ended up being instrumental in my diagnosis albeit some good luck was involved in getting to that point.  My twist of fate which involved a low hemoglobin score led me to a scan and ‘bingo’.  I had a ‘gastrointestinal blip’ some 18 months previously but that proved colonoscopy negative.  Despite my distant and metastatic tumour disposition and seemingly late diagnosis, I’m current non-syndromic due to “early” intervention and good treatment.  However, my ongoing treatment continues to play its part.

For many, the vague and routine symptoms generated by a syndrome contribute to the fact that NET Cancer is frequently misdiagnosed with some people suffering from the side effects for many years before a correct diagnosis is made.

There are many other less known syndromes that appear to be directly or indirectly connected with Neuroendocrine Tumours and I may update this post if I discover they are more prevalent than I think.  Please let me know if you’ve been told you have a NET related syndrome not listed.

Neuroendocrine Cancer – shh! Can you hear it? 

Thanks for reading


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  1. Linda Slater says:

    Thanks for your posts Ronny. I learn something new every time I read them. I was diagnosed with a neuroendocrine tumour last September 2017. I had been having explosive diarrhoea for a few years and bowel cramps which I thought was due to IBS. I work as an endoscopy nurse and had previously refused a colonoscopy having seen many a patient suffer a lot of pain during this procedure. But to cut a long story short I agreed to have one at a different trust to where I work. A number of polyps were removed during the colonoscopy, but the one containing the NET was in a caecal polyp, which was later found to have originated in the terminal illium 4.7cm. With liver, mediastinum, humerus and pelvic metastases. I was informed by the local NET team that the only treatment available was Somatostatin which I commenced on last November. I have been amazed at how quickly it stopped diarrhoea and hot flushes. It also stopped me having to get up for a pee several times a night. It improved my skin, I used to get frequent boils which I don’t now seem to get. These symptoms I never imagined could be anything to do with NET’S. But it’s too much of a coincidence for them not to be associated. I had also become intolerant to alcohol in the last couple of years before diagnoses. One or two sips of alcohol or a few spoons of sherry trifle and whoosh a big flush and bad headache – which is still a problem I discovered last night after couple of sips of shandy. Anyway, I asked to be referred to the Royal Free Hospital in London for a 2nd opinion. I’m pleased I did, as they have said my tumour is resectable, and other treatments are available. I am awaiting gallium PET scan and echocardiogram and, fingers crossed, I could be having surgery very soon, plus other treatments to extend my life from a previous prognosis of 5 years to possibly 20+ years. I would definitely recommend anyone diagnosed with NET’S to seek a 2nd opinion, and the Royal Free Hospital NET team are the best in the world. I thank God that I have the wherewithall to research my condition and to find out where I am going to receive the best care and treatment.


    Liked by 1 person

  2. Lauren says:

    Thanks for sharing this information. I will subscribe so I can keep reading!


    Liked by 1 person

  3. Jean Rodda says:

    Just for the record, no other reason except for someone else’s benefit, my only symptom, and that was just around the time of my diagnosis, was profuse sweating on the outer edges of my scalp. At an interview with a doctor, after my diagnosis, before meeting my surgeon, it was put down to hot flashes. I wanted to reply with what I was thinking but kept quiet. I certainly would have known by then what a hot flash felt like!!

    Liked by 1 person

  4. Deanna Vickery, Mrs says:

    Thankyou for this. the diagram is very interesting. I had late-diagnosed Cushings; the uncontrollable weight went on in the early ’80s. When I started having problems with my balance/vision in ’98 my Dr sent me for head MRI. Even this was misiagnosed by an ‘expert’ as Multiple Sclerosis and he took me into hospital to put me on a week of IV cortisol! I was saved by his Registrar who carefully read all my notes which showed abnormally high levels of cortisol, sent me for another MRI and correctly diagnosed a pituitary adenoma. This was removed in ’99 and after a year my weight went back to 9stone (from @ 13stone). Life got back to normal. Until 2011 when I suddenly had bouts of excruciating mid-gut pain about an hour after eating. To cut a long story short a midgut tumour was removed in Nov. 2011 along with a 60% liver resection due to metastisis.
    I never had any NET symptoms/syndrome until after the operations and new metastisis showed-up in a 2013 scan. That’s when I was put on 90mg monthly Lanreotide injections.
    But My symptoms are still not stable and I suffer with a mimick of IBS. My diet has been pruned as much as it can be. One day I’m ok, the next i have diaorrhea. It is a very isolating disease in that it’s so unpredictable. Gone are the days of eating out with friends/family.
    I’ve adjusted, but it’s a very lonely life….

    I really enjoy your blogs as they ‘understand’ – because, of course, you yourself are a sufferer.
    Grateful thanks,
    Dee Vickery

    Liked by 1 person

  5. Karen Long says:

    Would you mind emailing me a copy of the chart as well. I wish many physicians had a copy of this chart. Thank you – for this and all that you do.

    Liked by 1 person

  6. kimkmattke says:

    Im having my brain scans this morning and after yesterday’s results Dave and I have a guy feeling how these scans will turn out.. We have driven 240 miles and not one word!

    Liked by 1 person

  7. Marion Shead says:

    I wanted to copy the chart at the top, the one in different shades of blue, as I had many of those things before I was diagnosed. I still have many But it won’t copy. Any suggestions?

    Liked by 1 person

  8. cy says:

    Well Done! The same E’s do not apply to everyone. We each must find out what the culprits are in our syndrome. This disease is so frustrating!

    Liked by 1 person

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